The long path to NOAC*

Transcription

1 Ratschow Medal The long path to NOAC* A journey through time from a natural product to targeted anticoagulation S. Haas Formerly Klinikum Rechts der Isar, Technische Universität München, Germany Keywords Heparin, low molecular weight heparins, vitamin K antagonists, oral anticoagulants, NOAC Correspondence to: Prof. Dr. med. Sylvia Haas Normannenstr. 34a, München/Germany Tel /917191, Fax / sylvia.haas@thromboscientific.com Summary The discovery of anticoagulant drugs occurred at a time when the process of blood coagulation only had been roughly described and their mode of action was unknown. Nevertheless, heparin which was discovered 100 years ago and warfarin which was developed in the 1920s had taken off on a triumphal course which is unique in medical history. The synthesis of anticoagulants with targeted mode of action was only achieved at the end of the last century, e. g. the inhibitor of factor Xa fondaparinux or the recombinant production of the direct thrombin inhibitor hirudin, closely followed by the synthesis of the direct oral inhibitors of factor Xa and thrombin. These compounds had been clinically developed in the early 21 st century and meanwhile, they have become available for several indications. Dabigatran is the only thrombin inhibitor and rivaroxaban, apixaban and edoxaban are the three factor Xa inhibitors which entered the market and have started replacing the conventional anticoagulants for treatment of venous thromboembolic complications and for prevention of stroke in patients with atrial fibrillation. They have several characteristics in common such as a reproducible bioavailability, much shorter halflives than vitamin K antagonists, low interaction with other drugs, fixed dosing regimens without the necessity for routine coagulation controls and a better risk-/benefit profile than conventional anticoagulants. However, there are differences between the various compounds with regard to metabolism, renal elimination and the various dosing regimens which definitely need to be considered when prescribed to various patient populations. Schlüsselwörter Heparin, niedermolekulares Heparin, Vitamin- K-Antagonisten, orale Antikoagulanzien, NOAK Der lange Weg zu den NOAK Eine Zeitreise vom Naturprodukt zur gezielten Gerinnungshemmung Phlebologie 2016; 45: Received: June 27, 2016 Accepted: June 28, 2016 Zusammenfassung Vor 100 Jahren war der Ablauf der Blutgerinnung nur in groben Zügen bekannt und über den Wirkmechanismus des damals entdeckten gerinnungshemmenden Wirkstoffs Heparin gab es nur vage Vorstellungen. Infolge des raschen pragmatischen Einsatzes haben Heparin, so wie auch das in den 20er- Jahren entwickelte Warfarin, einen jahrzehntelangen Siegeszug angetreten. Erst gegen Ende des letzten Jahrhunderts gelang die Synthese von Antikoagulanzien mit gezieltem Wirkmechanismus, wie z. B. dem Faktor-Xa-Hemmer Fondaparinux oder die rekombinante Herstellung des direkten Thrombinhemmers Hirudin, dicht gefolgt von der Synthese der Nicht-Vitamin-K-antagonistischen oralen Antikoagulanzien (NOAK). Letztere wurden seit Anfang des 21. Jahrhunderts klinisch entwickelt und sind mittlerweile für verschiedene Indikationen verfügbar. NOAK zeichnen sich durch reproduzierbare orale Bioverfügbarkeit, kurze Halbwertszeit im Vergleich zu Vitamin- K-Antagonisten, geringe Interaktionen mit anderen Arzneimitteln, fixe Dosierung ohne Laborkontrolle sowie ein günstigeres Nutzen-/Risikoprofil als die konventionellen Gerinnungshemmer aus. Beim Einsatz dieser Präparate ist zu beachten, dass es Unterschiede in der Metabolisierung, der renalen Eliminierung und den Dosierungsregeln gibt. * This paper is essentially based on the lecture given by the author to the 57th Annual Congress of the German Society for Phlebology in Bamberg on the occasion of the presentation of the Max Ratschow medal, which was awarded by the Curatorium Angiologiae Internationalis in recognition of her lifetime s work. The long path to NOAC is thus also a summary of her academic life devoted to this topic and contains a corresponding excerpt of the list of publications in the literature.

2 246 S. Haas: The long path to NOAC Chance findings led to the first clinical uses of anticoagulants Heparin From canine brain to coagulation inhibition (1) At the start of the last century, the scientific interest of William Howell, physiologist at the John Hopkins Medical School in Baltimore ( Fig. 1), was chiefly on substances that affect blood clotting. He assumed that the cephalin he isolated from canine brain neutralised antithrombin and thereby enabled the calcium-induced activation of prothrombin (1). His medical student Jay McLean ( Fig. 2) was given the task of isolating cephalin, testing its purity and measuring the thromboplastin activity. McLean began by studying the literature: In my reading of the German chemical literature on phosphatides, I found articles by Erlandsen and Baskoff, in which they described extracts of heart and liver secured by a process similar to that for obtaining cephalin from brain (2). The two scientists had named these substances cuorin and heparphosphatide. Jay McLean therefore concentrated his search on the liver and made a significant finding, although the substance he found had anticoagulant rather than thromboplastic activity: I retested again and again until I was satisfied that an extract of liver possessed a strong anticoagulant action after its contained cephalin had lost its thromboplastic action. (2) This quote probably marks the time of the chance discovery of heparin one hundred years ago. McLean presented his results under the title The thromboplastic action of cephalin and left Baltimore shortly afterwards. William Howell continued the research and in 1918 isolated a second fat soluble anticoagulant that differed from the one previously isolated by McLean. Because it was isolated from the liver ( hepar in Greek), Howell called it heparin. Although the mechanism of action of heparin was not fully known and standardised formulations were not available, Howell s heparin very rapidly became used for the prevention and treatment of thromboembolic complications. Georg Haas, the founder of haemodialysis, started using heparin for his blood purification in 1927 ( Fig. 3). By the following year, Haas had carried out eleven haemodialysis treatments and published his results (3). Although, despite the observed side effects (e.g. headache, fever and vomiting), heparin remained on the market in its original composition of the natural product (4), the search began for a heparin preparation with a higher degree of purity, fewer side effects and more reliable efficacy in the prevention of thrombus formation. The Canadian Charles Best set himself these aims in 1928, but had to admit that, also for him, heparin was a difficult substance, not only in terms of its isolation, but even at the stage of extracting the crude drug. The autolysis that was necessary, in order to achieve a higher yield of heparin from the starting tissue led to such a strong, unpleasant odour that the procedure had to be moved from the laboratory to a farm. Best finally published the following purification protocol for heparin in 1933 (5): Take 2,300 kg intestines, 914 L water, 46 L chloroform and 23 L toluene. Heat to 36 C for 17 hours. Add 37 L acetic acid, 160 L ammonia, NaOH (to adjust the ph) and L water. Bring to the boil; then filter. Add 915 L hot water to the filtrate and leave to stand overnight, then remove the fat. Add pancreas extract, maintain for three days at 42 C, then bring to the boil. Filter off solid substances and check the amount of heparin in the liquid. As Best later admitted, the batches were not pure in the chemical sense, but were, however, largely free of toxic components. It was hoped that they were of uniform potency, but it was shown that problems occurred from batch to batch. Since the Canadian also made his substance available to other researchers, there was no shortage of criticism: the heparin sold caused failure of two experiments as well as damage to blood... if you intend to sell much more heparin, you should avoid such serious misbranding in the future (1). It was not until 1937 that Charles Best and his team dared to use their heparin clinically. After the successful experiment to prevent thrombi in dogs, came the first successful use in humans. The publication Heparin and the thrombosis of veins following injury by Donald Murray in 1937, marked the starting point for the clinical use of heparin to treat thromboses (6). Fig. 1 William Henry Howell ( ) Fig. 2 Jay McLean ( ) Phlebologie 4/2016 Schattauer 2016

3 S. Haas: The long path to NOAC 247 Vitamin K antagonists From sweet clover disease to the clinical use of warfarin and other vitamin K antagonists (1) A mysterious disease of cattle emerged in the United States and Canada in the 1920 s, shown by veterinary medicine investigations to be caused by internal haemorrhages. The trigger for this internal bleeding was found to be the feeding of animals with poorly dried clover and hay. In earlier times, the farmers had discarded damp and mouldy hay, but the economic depression in the 1920 s forced them to also use mouldy hay as feed. In 1929, the veterinary surgeon L. Roderick showed that the acquired coagulation disorder was caused by what he called a plasma prothrombin defect (4). The advice of the veterinary surgeon was simple Do not feed with spoiled hay. 10 years after the first outbreak of sweet clover disease, it was the farmer, Ed Carlson, who gave renewed impetus to the research. Like so many of his colleagues, he hadn t fully trusted the scientists and had continued to feed his cattle with mouldy hay. One night, after losing a number of his prize-winning cattle, he drove 200 miles in a blizzard to the nearest agricultural research station with a dead cow in his truck. There he is supposed to have placed a milk churn containing unclottable blood very roughly on the floor in front of the veterinary surgeon Karl Link. At first, all that Link could offer him was the long-known advice not to give damp hay and a blood transfusion. But, as was shown later, the churn with the uncoagulated blood was to alter the course of the history of blood clotting (7). Six years after the memorable encounter, Karl Link was able to isolate the substance in the damp hay that had caused the cattle to die, namely 3,3 -methylene-bis [4-hydroxycoumarin]. Through incorrect storage and fermentation, the natural coumarin present in freshly mown hay had been converted into a new substance that was to become known by the name dicoumarol. Fig. 3 Georg Haas: Haemodialysis in man Warfarin, an effective rat poison The cause of death of the cattle was thus identified and the race to exploit the new findings in a practical way began. But thrombosis prophylaxis was certainly not the prime target what Link was initially looking for was simply a better mousetrap! Since dicoumarol took too long to work (cattle did not show the first signs of the disease for 15 days and the animals died after 4 8 weeks), several variants of the naturally occurring coumarin were identified and tested. Number 42 on a list of 150 test substances seemed especially promising. The happy Karl Link named his discovery warfarin, because the Wisconsin Alumni Research Foundation had financed his research ( Fig. 4). From 1948 onwards, warfarin was eventually used with great success to combat the plague of rats (1). From rat poison to clinical application Fig. 4 Laboratory equipment of Karl Paul Link (Warfarin home exhibit, 1954) Similar to the previously outlined Ed Carlson-Karl Link story, the clinical development of warfarin is also associated with a particular coincidence. After a sailor completely recovered from an unsuccessful suicide attempt with warfarin in 1951, it was decided to conduct clinical trials on warfarin as a therapeutic anticoagulant. To avoid the association with the rat poison, the trade name Coumadin was selected for warfarin for human use and the drug was finally approved by the FDA in After the successful use of Coumadin one year later on Dwight Eisenhower, the President of the United States, who had suffered a myocardial infarction, Coumadin became widely used as the first available oral anticoagulant (1). In the 1950 s, the mechanism of action of warfarin was not yet understood, there were only indications that the effect of warfarin could be stopped by the administration of vitamin K. It was not until the 1970 s that the precise mechanism of action was elucidated (8). Briefly, warfarin prevents, in shot-gun fashion, both the hepatic synthesis of the biologically active forms of the vitamin K-dependent clotting factors II, VII, IX and X and of the antico- University of Wisconsin-Madison Archives, Image#S04531

4 248 S. Haas: The long path to NOAC agulatory acting substances protein C, protein S and protein Z. At the present time, warfarin is the most commonly used vitamin K antagonist worldwide. The drugs acenocoumarin and phenprocoumon, which belong to the same group of substances, are predominantly used in some parts of Europe and essentially differ only in their duration of action; phenprocoumon has the longest, with a normalisation time for clotting of 7 to 14 days after discontinuation of the drug. Low molecular weight heparins from pleiotropic to targeted mechanism of action Until the 1980 s, heparin in clinical use consisted of a mixture of several fractions, so it was called unfractionated heparin (UFH). Since studies suggested that heparins with defined and, in particular, lower molecular weight should have better properties, various low molecular weight heparins (LMWH) were produced using fractionation and fragmentation techniques. Although they differed with regard to their ratios of the inhibitory action of Factor Xa/ Factor IIa and other pharmacological parameters, unlike UFH, they could all be administered subcutaneously without routine laboratory monitoring. Furthermore, they had at least as good or even better efficacy, a lesser risk of bleeding and a lower potential of triggering a heparin-induced type II thrombocytopenia. Our research group was involved in many detailed investigations concerning the preclinical research and development of several LMWH preparations for the prophylaxis of venous thromboembolism (9 26). For example, in the first thrombosis treatment study with the LMWH certoparin, we investigated whether it should be administered subcutaneously or intravenously. This three-arm study, with approx. 130 patients in each group, compared the following treatment regimens with a treatment period of 14 to 16 days: certoparin perfusor-controlled IV, certoparin 8000 I.U. axa twice daily SC and UFH perfusorcontrolled IV. No advantage in terms of the primary endpoint (reduction in phlebographic Marder score) was observed with intravenous administration over subcutaneous administration. Bleeding occurred in 6.1 % of patients given UFH IV, in 11.7 % given certoparin IV, but only in 3.1 % of those who received certoparin SC. The large differences in the spread of the laboratory results in the two study arms with perfusor-controlled fixed daily dose of UFH and certoparin SC are shown graphically in Fig. 5 and Fig. 6. This led to the conclusion that no advantage is to be expected from an intravenous continuous infusion of certoparin compared to twice daily subcutaneous administration in a fixed dosage, particularly because no better efficacy or tolerability could be demonstrated in patients given certoparin intravenously (27). Fig. 5 Large spread of aptt results on non-laboratory adjusted, infusioncontrolled administration of 24,000 IU UFH/24h Fig. 6 Small spread of Heptests results with a fixed dose of 8,000 IU anti-xa certoparin SC Anticoagulants with selective inhibition of Factor Xa or thrombin Even though the low molecular weight heparins offer marked advantages in clinical use, some shortcomings nevertheless remain, such as the only reduced risk of HIT type II, the unspecific and indirect effect (via antithrombin), the decreased effectiveness in antithrombin deficiency and the exclusively parenteral administration. The course of the clotting cascade suggests that drugs with selective inhibition of Factor Xa or thrombin could be ideal anticoagulants. Whereas UFH unspecifically inhibits both thrombin and Factor Xa (anti-thrombin activity = anti-factor Xa activity), with the low molecular weight heparins the weighting is already shifted to Factor Xa inhibition (the ratio of anti-factor Xa/anti-thrombin should be at least 1.5). Although the concept of targeted Factor Xa inhibition was approached with LMWH, an intensive search was begun for even more specific drugs. Phlebologie 4/2016 Schattauer 2016

5 S. Haas: The long path to NOAC 249 Fondaparinux In the 1970 s, researchers showed that only one part of the heparin molecule binds to antithrombin. The pentasaccharide structure responsible for this was identified in 1980 and finally synthesized by Jean Choay in 1983 (28). He was also able to prove that his synthetic pentasaccharide specifically inhibited Factor Xa via antithrombin. After further years of development, in which the synthetic process was optimised and molecular modelling carried out, fondaparinux, the first structurally defined and synthetically manufactured pentasaccharide, was ready for clinical trials and was eventually introduced into clinical practice in It binds to antithrombin with high affinity and, as a result of its conformational change, leads to a rapid inhibition of Factor Xa. Later clinical trials showed that fondaparinux is significantly more effective than LMWH, especially in VTE high-risk prophylaxis in orthopaedic indications. In retrospect, it can be said that fondaparinux took the heparin story, which had begun in 1916, a decisive step forward: The complex mixtures of heterogeneous saccharides of animal origin with variations in their composition were replaced by a synthetic saccharide with a defined mechanism of action. A specific (indirect) inhibitor of Factor Xa was derived from a substance with multivalent antithrombotic effect including inhibition of thrombin and Factor Xa (1). Non-vitamin K antagonist oral anticoagulants (NOAC) Although a specific inhibition of Factor Xa was achieved with the synthetic pentasaccharide, fondaparinux, the mode of action is indirect and requires antithrombin as cofactor. The search therefore continued for direct Factor Xa and/or thrombin inhibitors, i.e. substances that act directly on the active centre. The ideal development goals for these new anticoagulants were: oral, wherever possible only once daily administration in a fixed dose and, if possible, with no adjustment for body weight, a wide therapeutic index, a predictable pharmacological action without routine monitoring, welltolerated (including no risk of drug-induced thrombocytopenia), no relevant interactions with foods or other drugs, a rapidly developing protection against thrombosis and a more favourable benefitrisk profile than previously available anticoagulants. With this goal in mind, new substances have been sought over the last twenty years with the prime aim of finding pharmacological properties that enable a direct and precisely defined intervention in the clotting system. This research has led to the clinical development of direct oral anticoagulants, which were called non-vitamin K antagonist oral anticoagulants (NOAC) to distinguish them from the vitamin K antagonists. There are now four NOAC products available for various indications the three Factor Xa inhibitors, rivaroxaban, apixaban and edoxaban, and the thrombin inhibitor dabigatran. The clinical development of these substances marked a new period in the clinical research work of the author. The so-called Proof of Concept began for all substances with dose-finding studies on thrombosis prophylaxis in patients undergoing elective hip or knee replacement, since these operations are associated with a high risk of thrombosis and bleeding. They have now become so well-standardised that they can be regarded as clinical models of thrombosis and bleeding for the clinical development of anticoagulants. The development programme of the oral Factor-Xa inhibitor rivaroxaban for the prophylaxis of venous thromboembolism included several studies on the question of whether the dosage should be once or twice daily (29, 30) as well as an extensive Phase III programme (RECORD studies), which showed superior efficacy with a comparable safety profile compared to prophylaxis with LMWH and led to the marketing authorisation of this substance for thromboembolism prophylaxis in elective hip and knee replacement surgery (31). The subsequent international XAMOS study investigated safety and efficacy of rivaroxaban in VTE prevention compared with conventional thrombosis prophylaxis in 17,413 orthopaedic patients following elective hip or knee replacement operations under routine conditions. Symptomatic thromboembolisms occurred less often under rivaroxaban than under conventional therapy namely in only 0.89 % of cases under rivaroxaban compared with 1.35 % of cases under the conventional therapy. Rates of major bleeding events were comparably low in both groups (0.40 % and 0.34 %) respectively. XAMOS thus confirmed the results of the RECORD trials programme (32). After extensive dose-finding studies (33), the clinical development of rivaroxaban for the treatment of venous thromboembolism included investigations of how and whether it could replace two anticoagulants (parenteral administration of heparins or fondaparinux and vitamin K antagonists). Finally, the EINSTEIN-DVT and EINSTEIN-PE studies with more than 8,000 patients showed that the single-drug approach was possible with rivaroxaban and that the clinical efficacy is not inferior to standard treatment (LMWH overlapping with and then followed by vitamin K antagonists (VKA)) (34). In addition, the rate of major bleeding events under rivaroxaban was 46 % lower than under LMWH/VKA therapy (HR 0.54 [95-%-CI: ], p = 0.002). The recently published XALIA study (35) was the first large-scale prospective observational investigation of the safety and efficacy of a NOAC rivaroxaban in DVT patients under routine clinical conditions. More than 5,000 patients with objectively confirmed DVT and for whom anticoagulation was indicated for at least three months could be included in this study. They received either rivaroxaban or treatment consisting of a parenterally administered LMWH, UFH or fondaparinux alone or initially overlapping, followed by an oral VKA (standard anticoagulation). The decision concerning the choice of treatment, dosage and duration of treatment was at the doctor s discretion and thus reflected clinical routine. Patients were followed up for at least 12 months and propensity score-adjusted analyses carried out to balance differences in the patient characteristics between the rivaroxaban group (n = 2 505) and the comparator group (n = 2 010). The rivaroxaban

6 250 S. Haas: The long path to NOAC patients were younger and had malignancies less frequently than in those patients given standard anticoagulation. The rate of major bleeding events in the rivaroxaban group was 0.8 %, compared to 2.1 % in the comparator arm (propensity score-adjusted HR 0.77; 95-%-CI: ; p = 0.44; n. s.). The rate of major bleeding events under rivaroxaban was also 0.8 % in the EINSTEIN-DVT Phase III study (36) The trend was also similar in XALIA for recurrent VTE and amounted to 1.4 % under rivaroxaban vs. 2.3 % in the comparator group (propensity score-adjusted HR 0.91; 95-%-CI: ; p= 0.72; n. s.). The comparison with EINSTEIN-DVT (incidence of recurrent VTE: 2.1 %) confirms an at least comparable efficacy of rivaroxaban under routine clinical conditions (35). A subgroup analysis (XALIA-DE) investigated whether the XALIA results were applicable to Germany. It was found that the incidence rates for major bleeding, recurrent VTE and all-cause mortality under rivaroxaban were likewise lower than under standard anticoagulation. This produced an overall favourable benefit-risk profile of rivaroxaban under routine conditions (37). Another important area of NOAC use is stroke prevention in patients with non-valvular atrial fibrillation. All four tested NOAC are likewise approved for this indication; dabigatran etexilate and apixaban as twice daily dosage and rivaroxaban and edoxaban as once daily. In a meta-analysis of all NOAC preparations, the authors Ruff et al. showed that the relative risk of stroke and systemic embolic events could be reduced by a highly significant 19 % compared to warfarin and all-cause mortality was also significantly lowered (38). When the higher dosages of NOAC were used, i.e. the regular dose to patients with normal renal function, the risk of major bleeding was comparable: there was a significant and clinically relevant reduction in intracranial haemorrhage compared to VKA (38). Safety and effectiveness of rivaroxaban were investigated in the Phase IV XAN- TUS study in a total of patients recruited in Europe, Canada and Israel (average CHADS2 score of 2.0). In the historical comparison with the Phase III ROCKET- AF study, in which patients with an average to high risk of stroke with an average CHADS2 score of 3.5 had been enrolled, major bleeding events occurred under treatment with rivaroxaban at an incidence rate of 2.1 per 100 patient-years compared to 3.6 per 100 patient-years in the ROCKET-AF study; the rate of gastrointestinal bleeding was also substantially lower than in ROCKET-AF. The XANTUS study thus confirmed the positive benefit-risk profile of rivaroxaban for the prevention of strokes in patients with atrial fibrillation (39). Post-marketing experiences with the thrombin inhibitor dabigatran etexilate were recorded in patients in the RELY-ABLE study over a mean observation period of 4.3 years. Patients in the Phase III RELY study had the option of continuing stroke prevention with this substance in the original divided dosage (110 mg or 150 mg each twice daily) under double blind conditions in the RELY-ABLE study. Data from this extension study confirmed, in principle, the results of RELY (40). The difference between RELY-ABLE and other Phase IV or registry studies is that patients in the RELY-ABLE study were enrolled into RELY under strict inclusion and exclusion criteria and treated and followed up by highly specialised investigators. This does not fully correspond to Conclusions To sum up, it can be said that the varied possibilities of the replacement of conventional anticoagulants by NOAC for the prevention and treatment of venous and cardiac thromboembolisms have led to clinically relevant advantages. Not least is their considerably simpler and safer handling in many indications, which has resulted in often decisive improvements in patient compliance and adherence to treatment. A look back at the first years of clinical use of NOAC provides a thoroughly positive balance to date in terms of the benefit-risk profile of these substances in everyday clinical practice. everyday clinical practice, where far more patients with more complex co-morbidities are treated by doctors without experience in the field of clinical studies. Therefore, Phase IV and registry studies with nonspecified inclusion criteria have a special informative value for routine patient care. Conflict of interest The author has received consultancy fees and honoraria for lectures from Aspen, Bayer, Bristol-Myers Squibb, Daiichi Sankyo and Sanofi. Ethical guidelines The manuscript was written without studies in humans or animals and as a review article refers to earlier original papers. References 1. Haas S, Gruber-Gerardy KF. Gerinnungsforschung Hundert Jahre vom Naturstoff zum direkten Xa- Inhibitor. Mainz: Medbrain Verlag McLean J. The discovery of heparin. Circulation 1959; 19: Haas G. Über Blutwaschung. Klinische Wochenschrift 1928;7: Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. Br J Haematol 2008; 141: Best CH. Preparation of Heparin and Its Use in the First Clinical Cases. Circulation 1959; 19: Murray DWG, Jacques LB, Perrett TS, et al. Heparin and thrombosis of veins following injury. Surgery 1937; 2: Duxberry BM, Poller L. The oral anticoagulant saga: past, present, and future. 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